tbuckley/cabot-search huggingface dataset:
Abstract 670: Distinct biochemical properties of KRAS Q61H mutant render cancer cells resistant to SHP2 inhibitors
Authors: Teklab Gebregiworgis, Yoshihito Kano, Michael Ohh, Christopher B. Marshall, Mitsuhiko Ikura
Journal: Cancer Research (2022)

Abstract Recent reports suggest that specific KRAS mutations are associated with either resistance or sensitivity of cancer cells to SHP2 inhibitors (SHP2i). However, a lack of understanding of the underlying mechanism(s) is hindering the clinical advancement of SHP2i therapy for cancer. Here we report that cancer cells that harbor KRAS Q61H mutation (found in about 5% of pancreatic ductal adenocarcinoma tumors) or HEK293 cells that over-express KRAS Q61H are resistant to SHP2i. Our biochemical studies supported by all atom molecular dynamic simulations show that the Q61H mutation impairs intrinsic GTP hydrolysis and impedes stimulation of the GTPase cycle by both SOS1 and RASA1, but has negligible impact on binding to BRAF-RBD. Similar to wild-type KRAS, the Q61H mutant can be phosphorylated by Src at Tyr-32 and Tyr-64, and both site scan be dephosphorylated by SHP2, although SHP2i does not reduce ERK phosphorylation in KRAS Q61H cells. In vitro, phosphorylation of KRAS Q61H increased intrinsic nucleotide exchange without affecting its insensitivity to SOS1 and RASA1. Phosphorylation of wild-type and SHP2i-sensitive mutants (e.g., G12V) confers resistance to SOS1/RASA1 activities and impairs binding to BRAF-RBD, thus the constitutive resistance to upstream regulation and uncompromised ability of phosphorylated KRAS Q61H to activate MAPK signaling are distinct properties of this mutant. Decoupling of KRAS Q61H from upstream signaling and impaired intrinsic nucleotide hydrolysis lead to a highly GTP-loaded pool that is insensitive to the suppressive effects of Src phosphorylation. While SHP2 plays multiple roles in stimulating RAS signaling, including promoting the GEF function of SOS1, reducing p120 GAP-mediated inactivation of KRAS, and reversing Src phosphorylation of KRAS, we revealed that none of these are required by KRAS Q61H. These insights provide a mechanistic understanding of oncogenic KRAS mutants that can guide clinical trials of SHP2 inhibitors for patients with pancreatic and other cancers bearing KRAS Q61H. Citation Format: Teklab Gebregiworgis, Yoshihito Kano, Michael Ohh, Christopher B. Marshall, Mitsuhiko Ikura. Distinct biochemical properties of KRAS Q61H mutant render cancer cells resistant to SHP2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 670.
Abstract 748: Role of LINC01614 in papillary thyroid cancer
Authors: Danielle Quaranto, Michelle Carnazza, Nicole DeSouza, Sina Dadafarin, Augustine Moscatello, Raj K. Tiwari, Jan Geliebter
Journal: Cancer Research (2022)

Abstract Papillary thyroid cancer (PTC) accounts for the vast majority of thyroid cancer cases (~80%), with a significantly higher prevalence in females, but much more aggressive and with poorer outcomes in males. Despite a high survival rate, disease recurrence and metastasis remain significant issues. Therefore, there is an unmet need for the elucidation and identification of molecular markers associated with PTC, to aid in identifying early-stage disease, as well as patient prognosis and therapeutic approaches. Long intergenic non-coding RNA (lincRNA) molecules comprise the largest subclass of RNA molecules within the human genome, yet the majority of their functions are yet to be identified. Evidence supports that these non-coding RNA molecules play a role in protein and RNA localization and scaffolding - implying a critical role in the fine tuning of gene expression. Recently, lincRNAs have been identified as major players in cancer development and progression. This deems lincRNAs as attractive, specific biomarkers and/or therapeutic targets, making them important aspects for further study. Data from our lab identified LINC01614 as being significantly upregulated (~10-fold increase) in PTC, when compared to normal thyroid tissue. There was also ~30-fold increase in LINC01614 in male PTC when compared to females, highlighting potential sex-related correlation for study. Thus, we are studying LINC01614 as a potential biomarker for diagnosis and prognosis, as well as a target for therapeutic intervention. LINC01614 was found to be upregulated in various thyroid cancer cell lines, with significant upregulation in the TPC1 (~5-fold; RET/PTC rearrangement) and K1 (~2-fold; BRAFV600E) cell lines when compared to the “normal”, immortalized thyroid cancer cell line (Nthy-ori-3-1). To decipher a phenotype for LINC01614 upregulation in PTC, we utilized the CRISPRi technique to decrease its expression in TPC1. The knockdown of LINC01614 resulted in a ~75% reduction in proliferation in TPC1 cells. Studies are underway to investigate the role of LINC01614 in migration, invasion, morphology, and tumorigenicity in TPC1 cells, as well as in the BRAFV600E cells, K1. Exploring the role that lincRNAs have in cancer phenotypes can lead to a plethora of different molecular markers for therapeutic intervention. The mechanisms by which these non-coding molecules regulate the expression of genes and other elements of the cellular milieu can serve as an open revenue for understanding how they impact PTC development and progression. Citation Format: Danielle Quaranto, Michelle Carnazza, Nicole DeSouza, Sina Dadafarin, Augustine Moscatello, Raj K. Tiwari, Jan Geliebter. Role of LINC01614 in papillary thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 748.
Abstract 780: Transcriptional profile of human pancreatic acinar ductal metaplasia
Authors: Corey Melissa Perkins, Jinmai Jiang, Hesamedin Hakimjavadi, Julie K. Bray, Alyssa Gosling, Lais da Silva, Gamze Bulut, Jamel Ali, Wendy Setiawan, Martha Campbell-Thompson, Srikar Chamala, Thomas D. Schmittgen
Journal: Cancer Research (2022)

Abstract Aberrant acinar to ductal metaplasia (ADM), one of the earliest events involved in exocrine pancreatic cancer development, is typically studied using pancreata from transgenic mouse models. We used primary, human pancreatic acinar cells to evaluate the transcriptional profile during the course of ADM. Following six days of culture on Matrigel, acinar cells underwent morphological and molecular changes reminiscent of ADM. RNA was sequenced from 14 donor’s paired pancreata (day 0 and 6 of culture). Unsupervised hierarchical clustering demonstrated complete separation of the gene expression profile between culture day 0 (acinar phenotype) and day 6 (ductal phenotype). By and large, acinar-specific genes were downregulated in the samples from day 6 ADM while ductal-specific genes were upregulated. Using a gene set enrichment approach, we identified regulons that are involved in regulating ADM including downregulated, acinar-associated transcription factors (including PTF1A, RBPJL, and XBP1) and upregulated, ductal- and progenitor-associated transcription factors (SOX11, SOX4, and YAP1). The expression of pancreatic cancer associated genes significantly correlated with the gene expression/regulon activity observed in normal pancreas undergoing ADM. We reported a detail analysis of the transcriptional profile during human ADM. Our findings confirm that many ADM-related transcription factors and signaling pathways discovered in transgenic mouse models are applicable to human ADM and highlights the relevancy of in vitro models of pancreas plasticity using human tissue. Citation Format: Corey Melissa Perkins, Jinmai Jiang, Hesamedin Hakimjavadi, Julie K. Bray, Alyssa Gosling, Lais da Silva, Gamze Bulut, Jamel Ali, Wendy Setiawan, Martha Campbell-Thompson, Srikar Chamala, Thomas D. Schmittgen. Transcriptional profile of human pancreatic acinar ductal metaplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 780.
Abstract 4131: Antitumor effects of ensartinib in non-small cell lung cancer harboring MET exon 14-skipping mutations
Authors: Yang Xia, Fen Lan, Jing Zhao, Hua-Hao Shen, Giovanni Selvaggi, Wen Li
Journal: Cancer Research (2022)

Abstract Background: Met proto-oncogene (MET) exon 14 skipping mutations are tumor drivers in approximately 3% of lung cancer patients. The antitumor efficacy of ensartinib, a novel multi-kinase inhibitor, against non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations was investigated in this study. Methods: The MET-mutant binding affinity and antitumor activity of ensartinib were assessed in vitro and in vivo. Preliminary therapeutic activity of ensartinib in patient-derived organoids was observed. To explore clinical activity, 17 NSCLC patients with MET exon 14 skipping mutations were treated with ensartinib at 225 mg qd. Results: Molecular dynamic simulations revealed that ensartinib exhibited favorable binding to c-MET. Ensartinib was highly effective in inhibiting the kinase activity of the MET exon 14 deletion protein (IC50 = 7.9 nM). Furthermore, ensartinib potently suppressed the MET pathway and the growth of Hs746T cells that were subcutaneously implanted into mice. Most importantly, of 17 patients with 14 different types of MET exon 14 skipping mutations undergoing ensartinib treatment, 1 (6%) showed a complete response, 11 (65%) achieved a partial response, and 4 (24%) exhibited stable disease. Thus, the objective response rate (ORR) was 71% and the disease control rate (DCR) was 94%, and the ORR in MET-TKI naive patients was even higher (12/15, 80%). In 2 patients with brain metastasis without prior brain radiation, we observed one partial response in the brain, while in the other patient the brain lesions were stable for 6 months. The most frequently reported adverse events were rash, peripheral edema, and nausea; however, no fatal adverse events occurred. Conclusions: These results provide the first evidence that ensartinib exhibits both preclinical and clinical antitumor activity against MET exon 14 skipping mutations with the potential of strong intracranial efficacy and warrant further evaluation in a planned phase II study thus providing more options to patients with MET exon 14 skipping mutations. Updated data including duration of response, PFS and and OS will be provided at the time of the presentation with additional few months of follow up. Citation Format: Yang Xia, Fen Lan, Jing Zhao, Hua-Hao Shen, Giovanni Selvaggi, Wen Li. Antitumor effects of ensartinib in non-small cell lung cancer harboring MET exon 14-skipping mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4131.
Abstract 5654: Degradation of Bcl-xL by DT2216 is lethal to T-cell acute lymphoblastic leukemia
Authors: Arunima S. Jaiswal, Elizabeth Williamson, Robert A. Hromas, Daohong Zhou
Journal: Cancer Research (2022)

Abstract Cancer is a multistep process where genomic and epigenomic alterations results in abnormal cellular proliferation and dissemination. This unregulated cellular proliferation can be interrupted through intervention therapy. One such strategy utilizes proteolysis targeting chimeras (PROTACs). PROTACs are heterobifunctional small molecular structures consisting of a ligand that binds to a target protein, and upon binding can recruit an E3 ligase which ubiquitinates the target protein, and eventually directs ubiquitinated protein for proteasomal degradation. This has been exploited as a revolutionary therapeutic strategy to degrade oncogenic and/or anti-apoptotic protein(s) that are overly expressed and offer a growth advantage in actively growing tumors. The accumulation of anti-apoptotic proteins creates resistance within the tumor against cancer treatments and preventative strategies in the clinical setting. In the present study, we used DT2216, a PROTAC that targets and promotes degradation of the anti-apoptotic protein Bcl-xL via the VHL (E3 ligase) pathway in T-cell acute lymphoblastic leukemia cells (T-ALL). Unlike other preclinical studies, like ABT263, DT2216 does not cause thrombocytopenia because VHL is poorly expressed in platelets. In our preclinical study, we treated thirteen human T-ALL cells with varying concentrations of DT2216 (0-1 µM) for 24 h and analyzed Bcl-xL expression by western blot analysis. Our data suggests that DT2216 results in the robust degradation of Bcl-xL in a dose-dependent manner at a minimal dose of 10 nM in eight of the cell lines studied (ALL-SIL, P12-Ichikawa, Jurkat, SUP-T1, HBP-ALL, HSB-2, PEER, and DND-41). Bcl-xL degradation triggers apoptosis, which was evident through the presence of cleaved products for Caspase-3 and PARP-1. We examined the expression of other anti-apoptotic proteins, Bcl-2 and Mcl-1 in response to DT2216 and neither protein was changed, which highlights DT2216’s specificity. We further evaluated the effect of DT2216 on the survival of T-ALL cells. Our data suggests that the IC50 for all the T-ALL cell lines ranges from 2-100 nM, with the exception of SUP-T1, which exhibited an IC50 above 1 µM. Our data suggests that DT2216 could serve as a viable, safe, and potent alternative or addition to traditional clinical treatments of T-ALL. Citation Format: Arunima S. Jaiswal, Elizabeth Williamson, Robert A. Hromas, Daohong Zhou. Degradation of Bcl-xL by DT2216 is lethal to T-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5654.
Abstract 5367: DNA-PKcs inhibitors impair OCT4-mediated <i>MYC</i> transcriptional activation in small cell lung cancer
Authors: Inhyoung Yang, Ismail Mohiuddin, Sung-Jen Wei, Martinez Gloria, Min H. Kang
Journal: Cancer Research (2022)

Abstract Small cell lung cancer (SCLC) is a disease found almost exclusively in smokers and is a highly aggressive cancer with incredibly poor outcomes. Initially, most patients diagnosed with SCLC respond to platinum + etoposide (PE)-based therapy, but relapse occurs in nearly all patients and is fatal. SCLC is a cancer with a heavy mutational burden, and loss-of-function mutations of the tumor suppressor genes RB1 and TP53 are nearly ubiquitous in SCLC tumors. Amplification and overexpression of the MYC of oncogene occurs in a subset of SCLC tumors that are associated with tumor progression, treatment resistance, and poor outcomes, therefore we pursued the inhibition of the MYC activation. The purpose of this study is to inhibit a novel pathway of MYC transcriptional activation via DNA-PKcs-mediated phosphorylation of OCT4 at its Ser93 residue in SCLC, a MYC transcriptional activation pathway that we discovered. We identified OCT4 being a transcription factor that primarily induce MYC activation. Subsequently, Serine 93 residue of OCT4, a new OCT-4 binding site, was phosphorylated by DNA-PKcs that was a critical step for OCT4-induced MYC activation. In a panel of 19 small cell lung cancer, DNA-PKcs, phosphorylation of OCT4 at Ser93, and c-MYC were positively correlated. We confirmed the binding of DNA-PKcs to OCT4 and identified novel OCT4-binding sites in the MYC promoter/enhancer region that regulated MYC expression via phosphorylation by DNA-PKcs, and DNA-PKcs or OCT4 knockdown decreased c-MYC expression. DNA-PKcs inhibitors also reduced phosphorylation of OCT4 at Ser93 leading to decreases in c-MYC and showed cytotoxic effects via inducing apoptosis by DNA-PKcs inhibitors. DNA-PKcs inhibitors augments antitumor activity of Bcl-2 inhibitors cell lines and xenograft models of small cell lung cancer. In conclusion, report here that DNA-PKcs-mediated phosphorylation of OCT4 at Ser93 is a novel mechanism for activating the MYC oncogene in SCLC, and that DNA-PKcs is a viable target to decrease c-MYC expression in these highly aggressive tumors. Citation Format: Inhyoung Yang, Ismail Mohiuddin, Sung-Jen Wei, Martinez Gloria, Min H. Kang. DNA-PKcs inhibitors impair OCT4-mediated MYC transcriptional activation in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5367.
De-escalating Chemotherapy for Advanced Extranodal Natural Killer/T-Cell Lymphoma
Authors: Kathryn Lurain, Thomas S. Uldrick
Journal: JAMA Oncology (2022)

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Abstract 3858: Peristalsis-like mechanical stimuli in the intestinal milieu promotes colorectal cancer invasion through GABAergic signaling changes in an organ-on-chip platform
Authors: Carly Strelez, Sujatha Chilakala, Kimya Ghaffarian, Ah Young Yoon, Jonathan Katz, Shannon M. Mumenthaler
Journal: Cancer Research (2022)

Abstract Mechanical forces in the tumor microenvironmental milieu are often understudied due to a lack of relevant preclinical model systems. Here we describe a microfluidic organ-on-chip platform that incorporates tissue-tissue interfaces and physical forces to aid in the examination of colorectal cancer (CRC) progression. A major advantage of this model is the ability to mimic peristalsis, a physiological process occurring in the gut. Live-cell imaging with a 3D printed organ-on-chip cradle was used to quantify the number of CRC cells that have invaded from the epithelial channel into the vascular channel over time. We determined that peristalsis-like motions in our organ-on-chip model enhanced the invasion capacity of CRC cells, mimicking intravasation. We subsequently examined the effluent media in stretched compared to non-stretched conditions using mass spectrometry based metabolomics and discovered an increase in the secretion of gamma-aminobutyric acid (GABA) by CRC cells, implicating peristalsis-mediated tumor cell invasion with neurotransmitter release. Inhibitors targeting the GABA-A receptor reversed the observed tumor cell invasion phenotype when cells were subjected to peristalsis-like motions. Interestingly, even in the absence of peristalsis, tumor cell invasion was promoted when GABA agonists were introduced into the organ-on-chip system. This work reveals important interactions between CRC cells and their microenvironment, and that disrupting GABAergic signaling might be an approach to prevent or delay cancer progression. Citation Format: Carly Strelez, Sujatha Chilakala, Kimya Ghaffarian, Ah Young Yoon, Jonathan Katz, Shannon M. Mumenthaler. Peristalsis-like mechanical stimuli in the intestinal milieu promotes colorectal cancer invasion through GABAergic signaling changes in an organ-on-chip platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3858.
Urologists and Kidney Transplantation: The First European Census
Authors: Alessio Pecoraro, Vincenzo Li Marzi, Francesco Sessa, Romain Boissier, Vital Hevia, Thomas Prudhomme, Iulia Andras, Alberto Breda, Sergio Serni, Angelo Territo, Riccardo Campi
Journal: European Urology (2022)
Abstract 6255: CRISPRa-mediated induction of apoptosis in therapy-resistant glioblastoma cells via derepression of pro-apoptotic genes
Authors: Ebru Yilmaz, Alisan Kayabolen, Semra Cemre Atalar, Buket Yigit, Burge Ulukan, Mujdat Zeybel, Tugba Bagci-Onder
Journal: Cancer Research (2022)

Abstract Induction of apoptosis in cancer cells via de-repressing dormant pro-apoptotic genes might be a successful therapeutic strategy. In this study, we utilized several dCas9-mediated CRISPR activation (CRISPRa) systems to activate two key pro-apoptotic genes DR4 and XAF1 in glioblastoma cells. CRISPRa is used to activate endogenous genes via either recruiting transcription factors or epigenetic modifiers to regulatory regions in the genome. Previously conducted studies showed that VPR, Suntag, and SAM systems are the most effective transcription factor-based systems for activating several genes in a variety of cell lines. However, epigenetic modifier-based systems that involve the recruitment of TET demethylases have more permanent effects. Therefore, we hypothesized that combinations of these systems may induce stronger activation. We systematically tested various CRISPRa systems and their combinations to activate XAF1 and DR4, which are known to be epigenetically silenced in drug-resistant glioblastoma cells. Inducing the expression of these genes, we aimed to observe apoptosis in glioblastoma cells either at a basal state or upon treatment with the pro-apoptotic ligand TRAIL. By transcriptomic alteration and cell viability analyses, we demonstrated that the combinatorial system including dCas9-TET1 and MS2-p65-hsf1 was the most efficient one for the activation of DR4 and XAF1 genes in both 293T and glioblastoma cells. Another system in which multiple TET1 enzymes were recruited to the gene promoter together with MS2-p65-hsf1 was found to be effective similarly, suggesting that the promoter demethylation is critical for the activation of these genes. Activation of these genes with the most efficient systems caused apoptosis and also sensitized glioblastoma cells to TRAIL treatment. Our preliminary work on measuring methylation levels of several CpG sites in the promoter regions of DR4 is in line with our observations of cell-based phenotypes. Together, our study indicates that the combination of transcription factor-based and demethylation-based CRISPR activation systems can induce pro-apoptotic gene expression in cancer cells and lead cancer cells to undergo apoptosis. Future applications of this methodology might involve the development of cancer-specific pro-apoptotic therapies. [E.Y. and A.K. contributed equally to this work.] Citation Format: Ebru Yilmaz, Alisan Kayabolen, Semra Cemre Atalar, Buket Yigit, Burge Ulukan, Mujdat Zeybel, Tugba Bagci-Onder. CRISPRa-mediated induction of apoptosis in therapy-resistant glioblastoma cells via derepression of pro-apoptotic genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6255.
Neutralization of the SARS-CoV-2 Omicron BA.4/5 and BA.2.12.1 Subvariants
Authors: Panke Qu, Julia Faraone, John P Evans, Xue Zou, Yi-Min Zheng, Claire Carlin, Joseph S Bednash, Gerard Lozanski, Rama K Mallampalli, Linda J Saif, Eugene M Oltz, Peter J Mohler, Richard J Gumina, Shan-Lu Liu
Journal: New England Journal of Medicine (2022)